Michiels on Dameshek — the evolving view of polycythemia vera

The image of William Dameshek hovers over myeloproliferative neoplasm – and hematology itself – like that of a founding father. In fact, much of contemporary diagnostics, research, and treatment of polycythemia vera are rooted in Dameshek’s work. Half a century before the sequencing of the human genome, decades before molecular biology had a toehold on reality, Dameshek grasped the basic clonal reality of MPNs and the appropriate treatment modalities.

Dr. William Dameshek Credit: Tufts photo archives

Perhaps it is possible to resolve all of these dilemmas, conflicts, antagonisms and confusions by considering, not that the various conditions listed are different but that they are closely inter-related. It is possible that these various conditions –”myeloproliferative disorders’” — are all somewhat variable manifestations of proliferative activity of the bone marrow cells, perhaps due to a hitherto undiscovered stimulus. This may affect the marrow cells differently or irregularly with the result that various syndromes, either clear-cut or transitional, result.

Contrary to persistent myth, Dameshek wasn’t the first to note or report on that commonality. In 1939 a British physiologist, Dame Janet Maria Vaughan, wrote: ‘It is suggested that polycythaemia vera, megakaryocytic leukaemia, and myelosclerosis with leuco-erythroblastic anaemia form a group of closely related conditions.’.And there were others with pieces of that puzzle at the dawn of the 20th Century, most notably Guglielmo, Osler, and Vaquez.

Nor was Dameshek first to consider the condition characterized by an excessive red blood cell mass as polycythemia. That honor probably falls to Louis Henri Vaquez, a French physician, who described PV in 1892 and attributed the increased red cell mass to overactive hematopoiesis.

In 1903, the legendary physician William Osler reported on several patients with ‘Chronic cyanosis, with polycythemia and enlarged spleen: a new clinical entity.’ His patients all had erythrocytosis, and some had palpable splenomegaly. He described them as suffering from Vasquez’s Disease.

Finally, Dameshek wasn’t the first to introduce venesection as a therapeutic intervention. The practice of bleeding to balance the Four Humors antedates Hippocrates and was practiced for two millennia before Dameshek came on the scene. But even here his role was revolutionary. He brought phlebotomy under rigid control, clearly demonstrating the effects of alternate approaches, determining the reasons for its efficacy and its limitations.

William Dameshek applied stringent scientific method and technique to the exploration of hematologic phenomena. He was prophetic in his ability to discern the likely etiology and progress of polycythermia vera. And his work opened hematologic therapeutic and investigative pathways that dominate MPN practice more than a half century later.

His work in polycythemia vera had natural implications for the development of hematology and the diagnostic significance of elevated hematocrit.

“….physicians and medical scientists have been fascinated by polycythemia — not because of its public health consequences, but because of the interesting clinical and physiologic implications of this group of diseases. Studies of polycythemia have contributed directly to many advances in our understanding of hematopoiesis and the regulation of red-cell production, including the role of erythropoietin. Furthermore, confirmation of the clonal origin of myeloproliferative disorders has derived, in part, from studies of patients with polycythemia vera. Erythrocytosis may be associated with a host of medical conditions,a fact that makes the clinical approach to an elevated hematocrit or hemoglobin level of considerable importance to primary care physicians.”

Dr. Jan Jacques Michiels‘ review, “Physiopathology, Etiologic Factors, Diagnosis, and Course of Polycythemia Vera as Related to Therapy According to William Dameshek, 1940-1950” appearsthis week in the Turkish Journal of Hematology. His overview of the formative years of PV discovery and treatment is illustrated with Dameshek’s own slides and sketches. Michiels also incorporates contemporary findings in molecular biology confirming Dameshek’s prescience.
Dameshek, says Michiels, sees true polycythemia, polycythemia vera, as a disorder where “all the stops are pulled,” a disorder “of the total bone marrow … in which erythrocytosis, leukocytosis, and thrombocytosis are all simultaneously present.” PV is a riotous expansion of red cells, white cells and platelets.

As far back as his 1950 article in the Journal of the American Medical Association, Dameshek advanced the idea that bone marrow might be stimulated by an unknown factor or factors. Another possibility he advanced for myeloproliferation was a failure in normal processes that would inhibit such expansion.

In 2005 when Vainchenker discovered the JAK2v617F mutation both possibilities were confirmed. As described by Michiels, the mutated JAK2v617F lost the inhibitory activity on its JH2 pseudokinase which would normally restrain the stimulation activity of the neighboring JHI kinase. Once turned loose, the JAK2’s JH1 kinase sensitized the hematpoietic stems cells to a cascade of proliferating influences, “the hematopoietic growth factors thrombopoietin, erythropoietin, insulin-like growth factor-1, stem cell factor, and granulocyte colony-stimulating factor, resulting in trilinear hypermyeloproliferation.”

Michiels traces Dameshek’s systematic approach to phlebotomy/iron deficiency therapy as deriving from his view that PV patients are fundamentally normal and the best approach is physiologic. He reserved use of the then-popular p32, a highly radioactive phosphorous isotope, for refractory cases and instances of major thrombosis.

Symptoms,signs and labs

In 1940, Dameshek offered a diagnostic algorithm for PV based on a group of symptoms, signs and lab reports. Direct examination of a patient coupled with analysis of blood and review of bone marrow slides were all part of his combined diagnostic procedure. Symptoms such as headache, visual disturbance, thrombosis, vascular disturbances of the extremities when combined with clear physical signs – splenomegaly, full appearance of the face, hepatomegaly, red hands and feet — plus data from bloodwork and bone marrow biopsy indicating high platelet count, elevated hematocrit and both red cell and megakaryocytic hyperplasia in bone marrow were “all essential before a definite diagnosis of PV can be made.”

“In PV, all stops to blood production in the bone marrow seem to have been pulled out. The marrow is crowded with great numbers of nucleated red cells and granulocytes in all stages of maturation and with megakaryocytes actively producing platelets.’

In 1950, Dameshek published “The Disease Polycythemia Vera” in the Journal of the American Medical Association (He had already started the journal Blood in 1946.) He may have published his advanced diagnostic criteria for PV in the more popular JAMA in order to provide PV diagnostic insights and therapeutic protocols to the general physician. It is here that he presents his findings on the impact of this unimpeded expansion of red blood cells, the expansion of total volume of blood.

“The great mass of blood in the circulation has at least three outstanding effects: (1) Plethora (2) decreased velocity of blood flow and (3) increased viscosity of the blood. The person with PV is actually ‘bursting with blood.’ All the various organs become distended with a superabundance of blood…This is particularly true of the brain, which is enclosed in the ‘closed box’ of the skull.”

His treatment of choice was “the systematic use of multiple venesections to reduce the red cell mass and the blood volume and to induce a state of iron deficiency…” To achieve this, his approach in 1946 was “to remove 500 cc of blood twice weekly for two to five weeks depending upon the initial hematocrit and hemoglobin levels….” To maintain the resulting state of iron deficiency somewhat longer, he wrote, “ it has been our practice to keep the patient on a diet low in iron.”

The effect of this regimen was not to reduce red cell formation but the iron starvation produced smaller red cells with lower hemoglobin and hematocrit level “for periods of six to 18 months during which time the patient may be completely asymptomatic.” The red cell levels continue to rise –erythrocythemia – but the quality of the cell has changed. At this point the best index of therapy is the hematocrit.

“The treatment of PV is a long-term project and it is best to consider the polycythemia patients as fundamentally normal,” wrote Dameshek. “As such they may have a long lifespan and every attempt should be made to keep the treatment as physiologic as possible.”

He saw two clear benefits from the venesection mode of therapy. “The red cell mass,hemoglobin and hematocrit are reduced to normal, whereas erythrocyte count remains increased above 6×109 and the bone marrow develops a state of iron deficiency with the result that erythrocytes produced are poorly hemoglobinized and microcytic. …”

“The reduction in iron reserve leads to an insufficient amount of iron for the synthesis of hemoglobin in the developing red cells and as a result the mature red cells produced are smaller than normal and occupy less room in the circulation than do normal-sized red cells. ….

“During the state of chronic iron deficiency, the patient himself presents a normal appearance. On this program it is possible to control patients with polycythemia for a few to many years. …:”

Dameshek was reluctant to use p32, a potentially dangerous radioactive isotope in patients with a relatively long life span. His comment on its use 65 years ago recalls the contemporary debate on hydroxyurea, a currently popular, effective and controversial drug. “ One naturally wonders,” wrote Dameshek, “whether the acute leukemic states that have occurred in some cases are due to the potentially leukemogenic drug or are associated with the polycythemia. The data at present up to 1950 are insufficient to permit statistical analysis at this point.”

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A very interesting article. I was concerned about the ever-diminishing size of my RBCs but now I see that this is a good thing, so it’s reassuring. This article gives a very clear picture of the disease and its implications. Thank you.